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The Journal of Immunology, 2007, 178: 3363-3367.
Copyright © 2007 by The American Association of Immunologists, Inc.

CUTTING EDGE

Cutting Edge: Antibody-Mediated TLR7-Dependent Recognition of Viral RNA1

Jennifer P. Wang2, Damon R. Asher, Melvin Chan, Evelyn A. Kurt-Jones and Robert W. Finberg

Department of Medicine, University of Massachusetts, Worcester, MA 01605


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
TLR7 recognizes the genome of ssRNA viruses such as Coxsackievirus B. Because TLR7 is expressed in intracellular compartments, viral RNA must be internalized before its recognition by TLR7. In this study, we define plasmacytoid dendritic cells (pDC) as peripheral blood mononuclear immune cells that respond to Coxsackievirus. pDC activation by Coxsackievirus B requires the presence of specific antiviral Abs. We show that Fc receptors mediate the recognition of virus-Ab complexes and that TLR7 is required for human and murine pDC production of cytokines. These data define a pathway by which intracellular TLR7 senses viral RNA and indicate a role for TLRs in association with Abs in sustaining virus-specific responses.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Plasmacytoid dendritic cells (pDC)3 are highly specialized cells that are important during viral infection, where they are recruited and can produce IFN-{alpha} (1). TLRs are crucial mediators in innate immune responses to pathogens. Of at least 11 TLR family members, TLR7 and TLR9 are expressed in pDC (2). These endosomal pattern-recognition receptors recognize viral genomic ssRNA and dsDNA, respectively, and engagement leads to the production of cytokines including IFN-{alpha} (3, 4, 5). IFN-{alpha} may be protective in the host response to many viruses, but proinflammatory cytokines activated by TLRs have the potential to adversely affect the host.

Igs play an essential role in the host defense against pathogens. However, they can also contribute to autoimmune diseases like systemic lupus erythematosus, in which high levels of Abs against nuclear Ags are present. Immune complexes (IC) comprised of either small nuclear ribonucleoprotein particles or chromatin can stimulate pDC to produce high amounts of IFN-{alpha} via TLR7 or TLR9, a phenomenon mediated by FcR (6, 7, 8, 9). IC may contribute to ssRNA viral diseases, including "atypical" measles, dengue hemorrhagic fever, and enhanced respiratory syncytial virus disease. Prior immune sensitization to such viruses can lead to overwhelming cytokine production and influx of inflammatory cells, and IC deposition has been implicated as a major disease-causing factor (10, 11, 12, 13, 14). Furthermore, recent studies have shown that IFN-{alpha} induction by certain viruses is enhanced in the presence of virus-specific Ig and is mediated by FcR (15, 16).

We define a role for virus-specific Ig activation of TLR7 by Coxsackievirus B (CVB), a nonenveloped, ssRNA picornavirus of the enterovirus group. CVB is commonly associated with subclinical human disease but can cause acute or chronic myocarditis. Myocardial damage may result from either cytolytic effects of CVB or from immune-mediated destruction (reviewed in Ref. 17). In our studies, we generated murine bone marrow-derived DC (BMDC) and found that they produce IFN-{alpha} and IL-12 p40 in response to CVB serotype 3 (CVB3) only in the presence of anti-CVB Abs. Human pDC also produce IFN-{alpha} in response to CVB3 only in conjunction with Ig. We demonstrate that both TLR7 and FcR participate in the virus-induced production of IFN-{alpha} by both murine and human pDC and that the presence of virus-specific Ab is essential.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Reagents

CVB3 strain Nancy was prepared as described previously (18) and for some experiments was UV-inactivated with 1 J/cm2 UVA light for 15 min. R-848 was a gift from D. Golenbock (University of Massachusetts, Worcester, MA). CpG 2336 was purchased from Coley Pharmaceuticals. Human AB serum was obtained from Sigma-Aldrich and Sandoglobulin intravenous immune globulin (IVIG) from Novartis. Anti-CVB3 mAb and IgG1 were purchased from Chemicon International, anti-CD64 and IgG2a from eBioscience, anti-CD32 from Abcam, and anti-CD16 from BD Pharmingen. Immunoregulatory DNA sequence (IRS) 661 was synthesized on a phosphorothioate backbone by MWG Biotech.

Mice

Fc{gamma}RIII–/– (B6.129P2-Fcgr3tm1Sjv) mice and Fc{gamma}RII–/– (B6.129-Fcgr2tm1) mice, each backcrossed 10 generations to C57BL/6, were obtained from The Jackson Laboratory. Fc receptor common {gamma}-chain-deficient (B6.129P2-Fcerg1tm1; backcrossed 12 generations to C57BL/6) mice were obtained from Taconic Farms. MyD88–/– (backcrossed 12 generations to C57BL/6) and TLR7–/– mice (backcrossed 7 generations to C57BL/6) were a gift from S. Akira (Osaka University, Osaka, Japan). Serum was obtained from whole blood of wild-type (WT) mice 12 days after infection with CVB3 (5000 PFU i.p.) or from uninfected control mice.

Cell culture

Human PBMC and pDC were isolated as previously described (19). Mouse bone marrow cells were cultured for 7 days with 10 ng/ml mouse fms-related tyrosine kinase 3 ligand (R&D Systems), resulting in a population of BMDC with 30–40% pDC by FACS staining. For some experiments, DC were sorted on a FACSAria (BD Biosciences) to isolate pDC (CD11c+CD11b–CD45R+). Mouse pDC purity was ≥98%.

Cytokines

Cell culture supernatants were collected at 18 h. ELISA was used to quantify human IFN-{alpha} (Bender MedSystems), murine IL-12 p40 (BD Biosciences), and murine IFN-{alpha} (PBL Biomedical Laboratories). Luminex testing was performed at the Baylor Luminex National Institute of Allergy and Infectious Diseases Core facility (Dallas, TX) for fibroblast growth factor basic, GM-CSF, IFN-{gamma}, IL-1{alpha}, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IFN-{gamma}-inducible protein 10, KC, MCP-1, MIG, MIP-1{alpha}, TNF-{alpha}, and vascular endothelial growth factor.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
Murine pDC activation by CVB3 requires specific anti-Coxsackievirus Ab

We examined Ab-mediated responses to CVB3 by murine BMDC. Incubation of bone marrow cells with fms-related tyrosine kinase 3 ligand results in a population of cells rich in pDC which secrete IL-12, IFN-{alpha}, and other cytokines in response to TLR7 and TLR9 ligands, including ssRNA viruses (3, 5, 20, 21, 22). We found that CVB3 did not induce IL-12 p40 production in BMDC unless opsonized with ≥1 µg/ml mAb specifically targeting CVB3. This combination led to vast production of IL-12 p40 (Fig. 1). At these concentrations, mAb neutralized CVB3, causing a decrease in viral plaque formation in HeLa cells by nearly 100-fold (data not shown). To confirm that in vivo infection leads to generation of specific antiviral Abs, we infected a mouse with CVB3 i.p. and collected serum 12 days later. Opsonization of CVB3 with this serum induced a strong IL-12 p40 response from DC, whereas opsonization with serum from a CVB3-naive, uninfected mouse did not. Under these conditions, UV-treated virus did not induce cytokines; either viral replication is required for DC activation or UV treatment alters the structure of viral RNA such that it can no longer engage with TLR7.


Figure 1
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  		FIGURE 1. CVB3 opsonized with anti-CVB3 Ab induces cytokine release from BMDC. Cells were stimulated with CVB3 (MOI, 100) opsonized with mAb targeting CVB3 or IgG2a isotype control (5 µg/ml). Cells were stimulated with CVB3 opsonized with serum obtained from a WT mouse 12 days postinfection with CVB3 (or uninfected control mouse serum). In some conditions, virus was UV-irradiated before opsonization. LPS (100 ng/ml), R-848 (3 µM), and CpG (3 µg/ml) were used as control ligands for TLR4, TLR7, and TLR9. Results are representative of three independent experiments. Error bars represent SD of triplicate samples.

 
Since BMDC are a mixed population, we used FACS to isolate a pure population of pDC and found that pDC produced cytokines in response to virus only in the presence of specific Abs. Using Luminex multiplex testing, we found several cytokines to be released by pDC, including IL-6, IL-12 p40, IFN-{gamma}-inducible protein 10, and MIP-1{alpha} (data not shown). All other tested cytokines were negative (see Materials and Methods).

Murine pDC activation by CVB3 IC requires expression of FcR common {gamma}-chain

We then asked whether opsonized CVB3 triggers cytokine responses by engagement with Fc{gamma}RI (CD64), Fc{gamma}RII (CD32), Fc{gamma}RIII (CD16), or Fc{gamma}RIV (reviewed in Ref. 23). We used BMDC from FcR{gamma} chain–/–, Fc{gamma}RII–/–, and Fc{gamma}RIII–/– mice to establish the role of FcR in the recognition of opsonized CVB3. Cells from FcR{gamma} chain–/– mice lack the {gamma}-chain subunit of FcR, which is essential for cell surface expression of Fc{gamma}RI, Fc{gamma}RIII, and Fc{gamma}RIV. FcR{gamma} chain–/– DC did not produce any IL-12 p40 or IFN-{alpha} in response to CVB3 opsonized with anti-CVB3 mAb (Fig. 2a), whereas DC from Fc{gamma}RII–/– and Fc{gamma}RIII–/– mice produced comparable amounts of cytokine to WT DC (Fig. 2b). Identical FcR requirements were observed with virus opsonized with serum from a CVB3-infected mouse (data not shown). Thus, either Fc{gamma}RI or Fc{gamma}RIV is required for cytokine induction by opsonized CVB3 in murine cells. This requirement is distinct from that of chromatin IC, which utilize murine Fc{gamma}III receptors for TLR9-mediated DC production of IL-12 p70 and TNF-{alpha} (8).


Figure 2
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  		FIGURE 2. The FcR common {gamma}-chain and TLR7 are required for IL-12 p40 and IFN-{alpha} production by opsonized CVB3. A, BMDC from WT C57BL/6 or FcR common {gamma}-chain-deficient (FcR{gamma} chain–/–) mice were stimulated with CVB3 (MOI, 100) opsonized with anti-CVB3 mAb or IgG2a isotype control at 5 µg/ml. B, BMDC from WT, FcR{gamma}II–/–, or FcR{gamma}III–/– mice were similarly tested. C, BMDC from WT, MyD88–/– mice, or TLR7–/– mice were also used. Control stimuli included LPS (100 ng/ml), R-848 (10 µM), and CpG (3 µg/ml) in all experiments. Results are representative of at least two independent experiments.

 
Murine DC activation by opsonized CVB3 requires TLR7 and MyD88

CVB, specifically its ssRNA genome, has been shown to interact with TLR7 and contribute to the production of inflammatory cytokines (24). We determined that TLR7 and the adapter molecule MyD88 are required for murine cytokine responses to opsonized CVB3 by using DC from mice deficient in these molecules. Induction of IL-12 p40 and IFN-{alpha} was absent from the cells from knockout mice (Fig. 2c); therefore, FcR-mediated delivery of viral RNA to intracellular TLR7 is critical for cytokine responses by pDC.

pDC are the primary responders among human PBMC to opsonized CVB3

Human PBMC demonstrate Ab-enhanced production of IFN-{alpha} in response to CVB (25). We examined IFN-{alpha} production in human PBMC in response to opsonized CVB3, testing three sources of Ig: autologous serum, serum from human male blood type AB (human AB serum), and pooled IVIG. Opsonization was performed by incubating virus with an equal volume of serum or IVIG for 15 min at 37°C before addition to cells. Each enabled dose-dependent production of IFN-{alpha} in response to live, but not UV-irradiated opsonized CVB3 (Fig. 3a). Unopsonized virus did not lead to any IFN-{alpha} production. Of note, in three independent experiments using PBMC from different adult donors, virus opsonized with autologous serum induced IFN-{alpha}. Nearly all adults are seropositive for CVB3, accounting for the presence of specific anti-CVB IgG in serum and IVIG (26).


Figure 3
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  		FIGURE 3. IFN-{alpha} production by human PBMC in response to CVB3 requires opsonization of virus and is predominantly from the pDC population. A, CVB3 (MOI, 100, 10, or 1) was opsonized with autologous serum, human IVIG, or human AB serum. For some conditions, CVB3 was UV-irradiated before opsonization. Results are representative of three independent experiments with different human donors. B, PBMC and PBMC depleted of pDC were stimulated with CVB3 opsonized with autologous serum. Controls included R-848 (20 µM) and CpG (10 µg/ml).

 
Given that pDC are strong IFN-{alpha} secretors, we suspected that pDC were responsible for the majority of the IFN-{alpha} produced by PBMC in response to CVB3. To generate a population of PBMC depleted of pDC, we added anti-CD304 MicroBeads to cells and passed them through a MACS Separator (Miltenyi Biotec). The resulting population of PBMC was largely devoid of pDC. When compared with the total PBMC population, pDC-depleted PBMC produced negligible IFN-{alpha} in response to opsonized CVB3 (Fig. 3b). pDC-depleted PBMC had equivalent IL-6 production following stimulation with the TLR2 ligand Pam3CSK4 (100 ng/ml) in comparison to total PBMC (16.1 ± 1.8 ng/ml vs 12.6 ± 2.7 ng/ml IL-6); therefore, altered viability of the pDC-depleted PBMC was not a contributing factor. Of positively selected pDC, high amounts of IFN-{alpha} were produced in response to opsonized CVB3 at a multiplicity of infection (MOI) of 30 (42.7 ± 8.8 ng/ml), whereas CVB3 alone did not induce IFN-{alpha}.

Human pDC activation by CVB3 is mediated by CD32 and TLR7

Recent studies investigating mechanisms of TLR activation have shown that CD32a (Fc{gamma}RIIa) is important for the activation of human pDC by IC involving small nuclear ribonucleoprotein particle or systemic lupus erythematosus-DNA (6, 7, 9). To establish the role for FcR in human pDC recognition of opsonized CVB3, we incubated pDC in the presence of neutralizing Abs against CD16 (Fc{gamma}RIII), CD32a (Fc{gamma}RIIa), or CD64 (Fc{gamma}RI) for 30 min before addition of stimuli. We found IFN-{alpha} responses to be mediated by CD32a, but not CD16 or CD64; results from a representative donor are shown in Fig. 4a. In experiments using multiple donors, anti-CD32a mAb (0.5 µg/ml) blocked virus-induced IFN-{alpha} production to 34 ± 5% compared with isotype control (n = 5, p < 0.01 by Student’s t test). Induction of IFN-{alpha} by R-848 was unaffected by the presence of neutralizing Ab (data not shown). Mice are naturally deficient in the CD32a isoform and only express the inhibitory CD32b (23), thus murine pDC must utilize a FcR other than CD32a to recognize Ab-virus complexes.


Figure 4
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  		FIGURE 4. IFN-{alpha} production by human pDC in response to opsonized CVB3 is mediated by CD32 and TLR7. A, pDC were stimulated with opsonized CVB3 (MOI, 30) in the presence or absence of increasing concentrations (0.1 or 0.5 µg/ml) of mAb against CD16, CD32, or CD64. *, p < 0.01 vs isotype-treated control, Student’s t test. B, pDC were stimulated with opsonized CVB3 (MOI, 30) in the presence or absence of IRS 661 (2.8 µM). Control stimuli included R-848 (1 µM) and CpG (10 µg/ml). *, p < 0.01 vs control, Student’s t test.

 
To confirm that human TLR7 participates in the response to opsonized CVB, pDC were treated with the TLR7 antagonist IRS 661 (27) for 30 min before addition of virus. IRS 661 significantly reduced IFN-{alpha} responses to opsonized CVB3 and R-848, but not the TLR9 agonist CpG (Fig. 4b). This result is consistent with findings reported by Yang et al. (28), who demonstrated that IFN-{alpha} production in human PBMC in response to CVB requires IRAK4, a signaling molecule in the TLR7 pathway. Of note, we did not detect expression of the Coxsackie and adenovirus receptor in human pDC by RT-PCR or FACS (data not shown).

Virus-specific Abs are generated during the early adaptive immune response to virus. The requirement of specific Ab for TLR-mediated viral recognition has implications for the quality of secondary immune responses and the evolution of autoimmune disease. Our data suggest that specific Abs allow previously nonresponsive DC to recognize the virus and to assist in viral clearance. Preexisting Abs generated during a previous infection could allow for immediate activation of pDC upon subsequent exposure to the virus and contribute to an effective secondary response.

Ab-mediated activation of cytokines in response to persistent viral infection may play a role in autoimmune diseases linked to CVB such as myocarditis. Since pDC can produce inflammatory cytokines and chemokines in response to viruses (21), Ab-mediated activation of innate immunity could promote inflammation at sites of infection. Activation of inflammatory cytokines could be associated with adverse outcomes. In a model of CVB3-induced myocarditis, MyD88-deficient mice had improved survival, decreased cardiac inflammation, and decreased levels of inflammatory cytokines in comparison to WT mice (29). Further in vivo studies will define the role for FcR and TLR7 in the presence of virus-specific Ab and may identify mechanisms by which immune sensitization to virus can cause disease.


   Acknowledgments
 
We thank A. Cerny for animal work and D. Libraty for helpful scientific discussion, assistance with Luminex samples, and FACS.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This research support was provided by National Institutes of Health Grants R01-AI049309 and R21-AI064681 (to R.W.F.) and K08-AI053542 (to J.P.W.). Back

2 Address correspondence and reprint requests to Dr. Jennifer Wang, Department of Medicine, University of Massachusetts, LRB 219, 364 Plantation, Worcester, MA 01605. E-mail address: jennifer.wang{at}umassmed.edu Back

3 Abbreviations used in this paper: pDC, plasmacytoid dendritic cell; BMDC, bone marrow-derived DC; CVB, Coxsackievirus B; IC, immune complex; IRS, immunoregulatory DNA sequence; MOI, multiplicity of infection; WT, wild type; IVIG, intravenous immune globulin. Back

Received for publication November 10, 2006. Accepted for publication January 12, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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